A neurodegeneration gene, WDR45, links impaired ferritinophagy to iron accumulation

• Published in: Journal of neurochemistry Vol. 160; no. 3; pp. 356 - 375
• Main Authors: Aring, Luisa, Choi, Eun‐Kyung, Kopera, Huira, Lanigan, Thomas, Iwase, Shigeki, Klionsky, Daniel J., Seo, Young Ah
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01-02-2022; John Wiley and Sons Inc
• Subjects: Accumulation; Animal models; Autophagy; Autophagy - genetics; BPAN; Brain; Brain Chemistry - genetics; Carrier Proteins - genetics; Cell Death; Cell Line; CRISPR; Defects; Degeneration; Ferritin; ferritinophagy; Gene Knockout Techniques; Genomes; Homology; Humans; Image acquisition; Iron; Iron - metabolism; Iron Overload - genetics; Iron Overload - metabolism; Mitochondria; Mitochondria - metabolism; Mutation; NBIA; Nervous system; Neurodegeneration; Neurodegenerative diseases; Neurodegenerative Diseases - genetics; Neurodegenerative Diseases - metabolism; Nutrient deficiency; Original; ORIGINAL ARTICLES; Proteins; Reactive Oxygen Species; Transferrin; Transferrin - metabolism; Transferrins; Yeasts; NBIA; neurodegeneration; ferritinophagy; iron; BPAN
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.15548

Neurodegeneration with brain iron accumulation (NBIA) is a clinically and genetically heterogeneous group of neurodegenerative diseases characterized by the abnormal accumulation of brain iron and the progressive degeneration of the nervous system. One of the recently identified subtypes of NBIA is β‐propeller protein‐associated neurodegeneration (BPAN). BPAN is caused by de novo mutations in the WDR45/WIPI4 (WD repeat domain 45) gene. WDR45 is one of the four mammalian homologs of yeast Atg18, a regulator of autophagy. WDR45 deficiency in BPAN patients and animal models may result in defects in autophagic flux. However, how WDR45 deficiency leads to brain iron overload remains unclear. To elucidate the role of WDR45, we generated a WDR45‐knockout (KO) SH‐SY5Y neuroblastoma cell line using CRISPR‐Cas9‐mediated genome editing. Using these cells, we demonstrated that the non‐TF (transferrin)‐bound iron pathway dominantly mediated the accumulation of iron. Moreover, the loss of WDR45 led to defects in ferritinophagy, a form of autophagy that degrades the iron storage protein ferritin. We showed that impaired ferritinophagy contributes to iron accumulation in WDR45‐KO cells. Iron accumulation was also detected in the mitochondria, which was accompanied by impaired mitochondrial respiration, elevated reactive oxygen species, and increased cell death. Thus, our study links WDR45 to specific iron acquisition pathways and ferritinophagy.
Cover Image for this issue:
https://doi.org/10.1111/jnc.15388
Schematic model for impact of WDR45 deficiency on iron accumulation, ferritinophagy, and cell death. WDR45‐deficient cells accumulate iron via the nontransferrin‐bound iron pathway (NTBI). The increased total iron levels were accompanied by an increase of the iron storage protein ferritin. WDR45 deficiency impairs ferritinophagy, the autophagic degradation of ferritin. Elevated iron levels were also detected in the mitochondria, which may impair mitochondrial function, elevate reactive oxygen species, and increase cell death.
Cover Image for this issue:
https://doi.org/10.1111/jnc.15388